Field of the Invention
The present invention generally relates to novel tau-specific binding molecules, particularly human antibodies as well as fragments, derivatives and variants thereof that recognize the tau protein, including pathologically phosphorylated tau and aggregated forms of tau. In addition, the present invention relates to pharmaceutical and diagnostic compositions comprising such binding molecules, antibodies and mimics thereof valuable both as a diagnostic tool to identify tau and toxic tau species in plasma and CSF and also in passive vaccination strategies for treating neurodegenerative tauopathies such as Alzheimer's disease (AD), amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS-PDC), argyrophilic grain dementia (AGD), British type amyloid angiopathy, cerebral amyloid angiopathy, corticobasal degeneration (CBD), Creutzfeldt-Jakob disease (CJD), dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration, Gerstmann-Sträussler-Scheinker disease, Hallervorden-Spatz disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Niemann-Pick disease type C (NP-C), non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease (PiD), postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle only dementia, multi-infarct dementia and ischemic stroke.
Background Art
Protein accumulation, modifications and aggregation are pathological aspects of numerous neurodegenerative diseases. Pathologically modified and aggregated tau including hyperphosphorylated tau conformers are an invariant hallmark of tauopathies and correlate with disease severity.
Tau is a microtubule-associated protein expressed in the central nervous system with a primary function to stabilize microtubules. There are six major isoforms of tau expressed mainly in the adult human brain, which are derived from a single gene by alternative splicing. Under pathological conditions, the tau protein becomes hyperphosphorylated, resulting in a loss of tubulin binding and destabilization of microtubules followed by the aggregation and deposition of tau in pathogenic neurofibrillary tangles. Disorders related to tau—collectively referred to as neurodegenerative tauopathies—are part of a group of protein misfolding disorders including Alzheimer's disease (AD), progressive supranuclear palsy, Pick's disease, corticobasal degeneration, FTDP′-17 among others. More than 40 mutations in tau gene have been reported to be associated with hereditary frontotemporal dementia demonstrating that tau gene mutations are sufficient to trigger neurodegeneration (Cairns et al., Am. J. Pathol. 171 (2007), 227-40). Studies in transgenic mice and cell culture indicate that in AD, tau pathology can be caused by a pathological cascade in which Aβ lies upstream of tau (Götz et al., Science 293 (2001), 1491-1495). Other finding however point to a dual-pathway model where both cascades function independently of each other (van de Nes et al., Acta Neuropathol. 111 (2006), 126-138). Immunotherapies targeting the beta-amyloid peptide in AD have produced encouraging, results in animal models and shown promise in clinical trials. More recent autopsy data from a small number of subjects suggests that clearance of beta-amyloid plaques in patients with progressed AD may not be sufficient to halt cognitive deterioration, emphasizing the need for additional therapeutic strategies for AD (Holmes et al., Lancet 372 (2008), 216-223; Boche et at, Acta Neuropathol. 120 (2010), 13-20). In the wake of the success of Abeta-based immunization therapy in transgenic animal models, the concept of active immunotherapy was expanded to the tau protein. Active vaccination of wild type mice using the tau protein was however found to induce the formation of neurofibrillary tangles, axonal damage and mononuclear infiltrates in the central nervous system, accompanied by neurologic deficits (Rosenmann et al., Arch Neurol. 63 (2006), 1459-1467). Subsequent studies in transgenic mouse lines using active vaccination with phosphorylated tau peptides revealed reduced brain levels of tau aggregates in the brain and slowed progression of behavior impairments (Sigurdsson, J. Alzheimers. Dis. 15 (2008), 157-168; Boimel et al., Exp. Neurol. 224 (2010), 472-485). These findings highlight the potential benefit but also the tremendous risks associated with active immunotherapy approaches targeting tau. Novel therapeutic strategies are urgently needed addressing pathological tau proteins with efficacious and safe therapy.
Passive immunization with human antibodies derived from healthy human subjects which are evolutionarily optimized and affinity matured by the human immune system would provide a promising new therapeutic avenue with a high probability for excellent efficacy and safety.